Pain Management during Ultrasound Guided Transvaginal Oocyte Retrieval - A Narrative Review

Patients should be evaluated for co-existing medical conditions before the administration of anaesthesia. With increasing age at conception and fertility treatment, it is crucial to evaluate women for possible associated medical conditions such as diabetes, hypertension and heart disease. Moreover, subfertile women may also have associated hypothyroidism, obesity, diabetes or hypertension or a history of tuberculosis or severe acute respiratory syndrome (SARS) COVID-19 in the past. They may be on drugs not only for the above-mentioned conditions but may also be on anticoagulants or psychiatric medications. All of these should be taken into consideration before deciding on the drug, the route of administration and the intra-operative and post-operative monitoring protocol. Special care should be taken for cancer patients who have presented for fertility preservation. Lately, ART is being done solely for the purpose of pre-implantation genetic testing for monogenic disorders. Patients undergoing the procedure may have conditions such as myotonic dystrophy, Marfan's syndrome or neurofibromatosis, which can influence the anaesthetic management and post-operative recovery.[ 92 ] Women with recurrent pregnancy loss due to antiphospholipid antibody syndrome may be on low-molecular-weight heparin injections and aspirin. Aspirin may be continued, whereas the last dose of heparin should be given at least 12 h before the procedure and the post-procedure dose should be administered 24 h later.[ 93 ] Patients were not taken up for ART during the initial days of the COVID-19 pandemic. When services resumed, ART procedures were done while abiding to the COVID-19 protocol. In our personal experience, patients were tested for the SARS coronavirus 2 infection before TVOR, and the procedure was cancelled if the result showed a positive status. In exceptional situations such as ovarian hyperstimulation syndrome (OHSS) or fertility preservation, it was decided to proceed with the TVOR after explaining the benefits and risks to the patient. As far as anaesthesia was concerned, both conscious sedation with analgesia and regional anaesthesia proved to be a safe option in these patients.[ 94 ] Cycle cancellation involves both mental and financial strain on the patient, especially in the Indian setting, where patients cannot avail of insurance for ART services. OHSS is one of the most dreaded complications of assisted reproduction. The supraphysiological hormone levels from the hyperstimulated and enlarged ovaries lead to the production of excessive inflammatory mediators including vasoendothelial growth factor. These changes ultimately result in increased capillary permeability and a shift of intravascular fluid to the third space. Although it is quite unusual for these changes to happen before oocyte retrieval, there are reports of the onset of symptoms within 24 h of administration of hCG.[ 95 ] Patients may present with complications ranging from varied levels of ascites to hypotension, hydrothorax or even pulmonary oedema and shock. These women require rapid-sequence induction for endotracheal intubation and airway protection. Fluid management must be meticulous and patients may require an arterial or central venous line for both fluid administration and adjustment to maintain perfusion and avoid fluid overload and consequences due to increased capillary permeability. In case of extensive ascites or hydrothorax, paracentesis or thoracocentesis may be planned before the administration of GA to improve the respiratory reserve.[ 96 ]

Pain experienced during oocyte retrieval is due to the needle piercing the vaginal wall and stretching and piercing of the ovarian capsule. At present, conscious sedation is the most preferred method while the other practiced techniques are general anaesthesia (GA), regional or local anaesthesia.[ 2 ] Apart from providing safe analgesia with fewer adverse effects, the other major concern when it comes to anaesthesia for assisted reproduction is the presence of the anaesthetic drug in the follicular fluid and its possible effects on the oocyte quality and thereby the pregnancy rates. Follicular fluid concentration of the anaesthetic agents plays a major role in the oocyte quality, fertilisation and implantation rates. Prolonged exposure to certain agents can result in significantly lower pregnancy and live birth rates.[ 3 ] Although there have been studies on performing TVOR without analgesia, present day clinicians would prefer administering analgesia and/or anaesthesia, especially when there are drugs which are currently considered quite safe and effective.[ 4 ] Medline, Embase, PubMed and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines. We included relevant articles published between the years 1987 and 2022. We have excluded animal studies and studies on anaesthesia for laparoscopic oocyte retrieval from this review. Conscious sedation and analgesia (CSA) or procedural sedation is the most common route of anaesthesia administered for women undergoing TVOR.[ 5 ] This is the preferred mode of anaesthesia in 95% and 84% of IVF centres in the USA and UK, respectively.[ 2 6 7 ] Physician and patient satisfaction are better with CSA as most of the drugs used are also potent anxiolytics and depression in the level of consciousness is much lesser when compared to GA, thereby not necessitating assisted airway support throughout the surgical procedure.[ 8 9 ] The American College of Emergency Physicians mentions CSA as a ’technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function. CSA is intended to result in a depressed level of consciousness that allows the patient to maintain oxygenation and airway control independently.’[ 10 ] With meticulous administration, these drugs have the least short-term and long-term side effects, are well-tolerated and the ease of delivery is also better when compared to other modes of anaesthesia [ Table 1 ].[ 6 11 ] A patient on CSA should be monitored as per the American Society of Anesthesiology monitoring system. Monitored anaesthesia care, conscious sedation and analgesia, total intravenous anaesthesia TIVA=Total intravenous anaesthesia, MAC=Monitored anaesthesia care, CSA=Conscious sedation and analgesia, TVOR=Transvaginal oocyte retrieval, GA=General anaesthesia, PCS=Patient-controlled sedation, PAS=Physician-administered sedation, FM=Face mask, ETT=Endotracheal tube, LMA=Laryngeal mask airway, PACU=Post-anaesthesia care unit, ART=Assisted reproductive techniques GA was the technique of choice during the earlier days of ART. The anaesthetic agents used are either intravenous; such as propofol, ketamine, opioids or benzodiazepines; or inhalational agents such as nitrous oxide ( N 2 O) and vapours of isoflurane, desflurane and sevoflurane [ Table 2 ]. Isoflurane is the most commonly used drug due to its low blood gas solubility when compared to halothane and thereby has lesser central nervous system effects.[ 17 ] Patients may be kept on either spontaneous ventilation through face mask or laryngeal mask airway or mechanically ventilated through laryngeal mask airway or endotracheal tube. Apart from the less favourable effects such as prolonged recovery and post-operative nausea and vomiting, studies have also shown adverse ART outcomes such as reduced fertilisation and pregnancy rates when halogenated fluorocarbons with nitrous oxide were used.[ 3 ] The use of N 2 O for GA during oocyte retrieval is controversial as many studies have shown a detrimental effect on embryos.[ 22 ] There was a recent case report on violent cough following GA with propofol and pentazocine, which resulted in ovarian haemorrhage and severe haemoperitoneum.[ 23 ] GA may be the preferred mode of anaesthesia in selected situations such as,[ 24 ] General anaesthesia TIVA: Total intravenous anaesthesia, GA=General anaesthesia, LMA=Laryngeal mask airway, ETT=Endotracheal tube, FM=Face mask, MAC=Monitored anaesthesia care Anxiety or other psychological issues When longer procedure time or more manipulation due to the difficult procedure is expected in cases such as endometriosis/endometrioma, pelvic adhesions or difficult-to-access ovaries Adverse effects during conscious sedation/regional anaesthesia in previous attempts. Anxiety or other psychological issues When longer procedure time or more manipulation due to the difficult procedure is expected in cases such as endometriosis/endometrioma, pelvic adhesions or difficult-to-access ovaries Adverse effects during conscious sedation/regional anaesthesia in previous attempts. Literature from the earlier days of ART suggested the significant negative impact of GA on fertilisation, cleavage rates and embryo quality. There is a fair chance that the CO2 pneumoperitoneum which was created for laparoscopic oocyte retrieval could have also contributed to these findings significantly.[ 3 25 ] Although conventionally anaesthesia administration is performed by physicians, patient-controlled analgesia (PCA) offers patients control over the drug administration as per their requirements. PCA has been considered an effective alternative to physician-administered anaesthesia, especially in low-resource settings and also for patients with low ovarian reserve undergoing TVOR where the duration of the procedure may be very less [ Table 3 ]. Patient-controlled analgesia PCA=Patient controlled analgesia, PAS=Physician-administered sedation, PCS=Patient-controlled sedation, TIVA=Total intravenous anaesthesia, SD=Standard deviation In women undergoing ART, regional anaesthesia has the advantage of minimal systemic absorption of the local anaesthetic agent and thereby very minimal follicular fluid concentration. Studies comparing regional anaesthesia with sedation and GA have not shown gross differences in anaesthetic parameters or ART outcomes [ Table 4 ]. Regional anaesthesia-spinal anaesthesia, epidural anaesthesia TVOR=Transvaginal oocyte retrieval, TIVA=Total intravenous anaesthesia, MAC=Monitored anaesthesia care, GA=General anaesthesia, PCB=Paracervical, CSA=Conscious sedation and analgesia, ART=Assisted reproductive techniques, CI=Confidence interval, OR=Odds ratio, EA=Epidural anaesthesia, SA=Spinal anaesthesia, EMLA=Eutectic mixture of local anaesthetics, MII oocyte=Metaphase II oocyte Paracervical (PCB) and pre-ovarian block (POB) involve injecting a local anaesthetic agent adjacent to the respective neural plexus. The paracervical block is performed under sterile conditions, with the patient in the lithotomy position. The local anaesthetic agent is injected through the cervicovaginal fornix and deposited around the cervix at four locations, usually at the 1,5,7 and 11 o’clock positions. The pre-ovarian block is performed under ultrasound guidance, by infiltrating the local anaesthetic agent in the vaginal wall and peritoneal surface adjacent to the ovary [ Table 5 ]. Paracervical and pre-ovarian block GA=GA=General anaesthesia, PCB=Paracervical, TIVA=Total intravenous anaesthesia, POB=Pre-ovarian block, CSA=Conscious sedation and analgesia, TVOR=Transvaginal oocyte retrieval Drugs used for anaesthesia and their dosage plays a major role in the anaesthetic management as well as the ART outcome [ Table 6 ]. For providing sedation, most anaesthesiologists prefer midazolam and/or propofol with fentanyl. Choosing the right drug is extremely important as it not only involves patient safety, but the outcome may also be affected if the drug accumulates in the follicular fluid. Midazolam is the most preferred benzodiazepine due to its potent sedative and anxiolytic properties. When combined with opioids, the synergistic action is known to provide better analgesic effect.[ 8 ] The combined action also necessitates lesser dose requirement for both drugs. A randomized trial published in 2008 concluded that side effects were lesser with midazolam and fentanyl combination when compared to propofol and fentanyl.[ 57 ] While considering opioid administration, remifentanil has proved to be better than fentanyl in terms of faster recovery.[ 58 ] Drugs TVOR=Transvaginal oocyte retrieval, ART=Assisted reproductive techniques, CI=Confidence interval, PACU=Post-anaesthesia care unit, IQR: Interquartile range, PG=Prostaglandin, CRH=Corticotropin releasing hormone, ACTH=Adrenocorticotropic hormone Propofol is used both for conscious sedation as well as GA. It has both sedative and analgesic properties and the advantage of faster onset, short elimination time and lesser incidence of post-operative nausea and vomiting.[ 17 ] Daycare procedures such as TVOR require drugs with a shorter half-life which aids in rapid weaning from anaesthesia. Both patient and physician satisfaction are better when there is early awakening and orientation to time with quick return of normal psychomotor performance. The rapid metabolisation of propofol in the liver aids in accelerated clearance from the system and thereby faster recovery when compared to other intravenous anaesthetic agents.[ 17 ] There is a dose-dependent incidence of respiratory and myocardial depression with propofol, which can be overcome by combined administration of an opioid such as fentanyl. The follicular fluid concentration of propofol was also found to be dose-dependent.[ 59 ] There was no difference in ART outcome in terms of fertilisation, cleavage, implantation or abortion rates when compared with thiopental. Propofol requirement was found to more in patients who were highly anxious before the procedure.[ 60 ] Ketamine belongs to the phencyclidine family of drugs and causes dissociative anaesthesia through a central neurological action. Due to its additional properties such as analgesic effect, loss of consciousness and anterograde amnesia without cardiorespiratory depression, it was once considered an ideal anaesthetic agent, both for GA and conscious sedation. Yet, the drug lost its popularity due to its undesirable post-operative effects such as vivid dreaming, illusions and feelings of fear or excitement which persist for considerable several hours. Various other modalities such as electroacupuncture and acupressure have also been suggested for pain management during oocyte retrieval.[ 87 88 ] Although these techniques have provided better pain relief when combined with intravenous sedation, they have not been quite helpful as a stand-alone treatment for intra-or post-operative pain relief.[ 89 ] Simple and inexpensive interventions such as music therapy can also reduce pain scores and patient anxiety and improve patient satisfaction.[ 90 ] A booklet for coping intervention for oocyte retrieval was developed by a psychologist. The booklet has information about the oocyte retrieval procedure in detail, including pain and possible outcomes and coping strategies such as muscle relaxation, distraction techniques, deep breathing and positive reappraisal. These coping strategies may also improve patient satisfaction and recovery.[ 91 ]

Assisted reproductive techniques (ARTs) in the form of in vitro fertilisation (IVF) or intracytoplasmic sperm injection are interventions that include in vitro handling of gametes or embryos for the purpose of reproduction. It is either the final recourse in many couples with unexplained infertility of long duration or the only option in women with bilateral tubal block and men with azoospermia who undergo surgical sperm retrieval. With increasing awareness and improvised techniques, the number of patients who opt for these treatment modalities is constantly on the rise. Women undergoing ART require ovarian stimulation with gonadotropins followed by oocyte retrieval. During the earlier stages of ART, oocyte retrieval was done laparoscopically. Dr. Subas Mukherjee created India's first IVF baby and the world's second IVF baby (born just 67 days after the world's first IVF baby on 3 rd October 1978) by retrieving oocytes through the transvaginal approach. His great contribution was not recognised and the first reported transvaginal oocyte retrieval (TVOR) was many years later in the year 1984.[ 1 ] At present, the ultrasound-guided transvaginal approach is widely practiced for oocyte retrieval. Although the procedure is less invasive when compared to the transabdominal or laparoscopic approach, the women can experience significant pain during the procedure which demands the need for anaesthesia. This review discusses the various available methods for pain management during TVOR in women with and without associated comorbidities. The outcomes that were focused on, were pain relief during the procedure, physician and patient satisfaction, adverse effects, effect on the oocyte quality and embryo development and ART outcome. The review was written to provide insight into the methods that provide adequate pain relief with fewer side effects and the least impact on oocyte quality and embryo development.

In recent times, both patient and specialist prefer an anaesthetic modality which provides early recovery with the least adverse effects. For TVOR especially, women prefer alternatives to GA for faster recovery, cost-effectiveness or for the fear of anaesthesia.[ 97 98 ] No single technique or drug has been identified as the best choice for TVOR. Yet, it is the duty of the physician and the anaesthesiologist to individualise and identify the best suitable modality for every woman, discuss the available techniques and the reason for suggesting a particular modality for her, its advantages and possible adverse effects. According to this review, conscious sedation appears to be the most preferred mode of anaesthesia in women undergoing TVOR owing to its fewer adverse effects, faster recovery, better patient and specialist comfort and the least effect on oocyte quality and embryo development. Combining it with paracervical block resulted in lesser consumption of the anaesthetic drug, which may have a beneficial effect on the oocyte quality. Therefore, a multimodal approach may be able to provide effective pain relief and better recovery with fewer adverse effects. Nil. There are no conflicts of interest.

This review includes research articles on all modalities of pain relief administered during TVOR. There was no strong evidence to prove that a particular anaesthetic technique was better than the rest. Conscious sedation provided better patient and physician satisfaction due to faster recovery and lesser adverse effects when compared to GA.[ 13 14 ] Although the ART outcome was similar in both groups, some studies have shown a negative effect when nitrous oxide was used.[ 14 ] Similarly, the administration of opioids along with CSA or GA was found to be beneficial with regard to recovery, adverse effects and ART outcome.[ 8 ] Intraoperative pain was significantly higher with PCA when compared to the other modalities, although there was no difference in pregnancy rates.[ 15 31 ] Paracervical block alone may not provide adequate pain relief unless it is combined with another modality such as conscious sedation[ 45 ] or GA,[ 56 ] whereas remifentanil[ 49 ] or propofol[ 50 ] when combined with PCB provides better pain relief and also reduces the requirement of the anaesthetic drug. Various doses of lignocaine have been tried and 50 mg of lignocaine for PCB has proven to be effective in managing pain.[ 47 ] Post-operative side effects such as nausea and vomiting are common with GA or CSA when compared to regional anaesthesia.[ 33 ] A recent Indian study suggested that the incidence of nausea and vomiting was more with the use of opioids and that the use of dexmedetomidine instead of fentanyl improved symptoms.[ 78 ] Studies have not compared regional anaesthesia with GA or CSA in terms of ambulation, but the use of 1.5% lidocaine resulted in earlier ambulation when compared to 5% lidocaine,[ 32 ] whereas the addition of fentanyl to 1.5% lidocaine did not alter the time to ambulation.[ 80 ] In our experience, both physicians and patients prefer CSA or TIVA when compared to EA/SA for earlier ambulation and lesser duration of hospital stay. Although GA may provide the best pain relief, disadvantages such as prolonged recovery, need for assisted ventilation, post-operative side effects and the cost factor makes it less favourable when compared to CSA. Although the review is a compilation of the available evidence for pain relief, statistical analysis was not done to pool the evidence due to the heterogeneity of the studies, different study designs, comparators, dosage and types of drugs. Moreover, the ART outcome also depends on numerous variables and is not confined to the mode of anaesthesia and the anaesthetic drugs alone.